Safety and feasibility of continuous ketamine infusion for analgosedation in medical and cardiac ICU patients who received mechanical ventilation support: A retrospective cohort study

Purpose To assess the effect of continuous ketamine administration in patients admitted to medical and cardiac intensive care units (ICUs) and received mechanical ventilation support. Methods We conducted a retrospective cohort study between March 2012 and June 2020 at an academy-affiliated tertiary hospital. Adult patients who received mechanical ventilation support for over 24 h and continuous ketamine infusion for at least 8 h were included. The primary outcome was immediate hemodynamic safety after continuous ketamine infusion. The secondary outcomes included immediate delirium, pain, and use of sedation. Results Of all 12,534 medical and cardiac ICU patients, 564 were eligible for the analysis. Ketamine was used for 33.3 (19.0–67.5) h and the median continuous infusion dose was 0.11 (0.06–0.23) mcg/kg/h. Of all patients, 469 (83.2%) received continuous ketamine infusion concomitant with analgosedation. Blood pressure and vasopressor inotropic scores did not change after continuous ketamine infusion. Heart rate decreased significantly from 106.9 (91.4–120.9) at 8 h before ketamine initiation to 99.8% (83.9–114.4) at 24 h after ketamine initiation. In addition, the respiratory rate decreased from 21.7 (18.6–25.4) at 8 h before ketamine initiation to 20.1 (17.0–23.0) at 24 h after ketamine initiation. Overall opioid usage was significantly reduced: 3.0 (0.0–6.0) mcg/kg/h as fentanyl equivalent dose at 8 h before ketamine initiation to 1.0 (0.0–4.1) mcg/kg/h as fentanyl equivalent dose at 24 h post-ketamine initiation. However, the use of sedatives and antipsychotic medications did not decrease. In addition, ketamine did not increase the incidence of delirium within 24 h after ketamine infusion. Conclusion Ketamine may be a safe and feasible analgesic for medical and cardiac ICU patients who received mechanical ventilation support as an opioid-sparing agent without adverse hemodynamic effects.


Introduction
Analgesia and sedation are essential elements of care for mechanically ventilated patients in the intensive care unit (ICU). Although the 2018 clinical practice guidelines for adult patients in the ICU recommended light sedation and early mobilization, some mechanically ventilated patients require deep sedation during the early phase of acute respiratory distress syndrome management [1,2]. For deep sedation, intravenous administration of opioids, benzodiazepines, and propofol is often preferred in the ICU. However, their use is associated with complications, including dependence, delirium, and adverse hemodynamic changes.
Ketamine is a non-competitive N-methyl-D-aspartate receptor antagonist that blocks glutamate and induces both analgesia and sedation [3]. A recent meta-analysis reported an increasing trend of ketamine use in mechanically ventilated patients and showed that ketamine might be used as a sedative-sparing agent [4]. In addition, several randomized control trials demonstrated the clinical benefits of continuous ketamine infusion in critically ill patients [5,6]. The respiratory drive is preserved with a chronotropic effect on the cardiovascular system at therapeutic doses. However, most previous studies were conducted with small sample sizes in trauma, postoperative, or cerebral ischemia patients. Therefore, the usefulness of continuous ketamine infusion was not supported in the medical and cardiac ICUs, where many mechanically ventilated patients are often admitted.
This study assessed serial hemodynamic, pain, agitation, and sedation trends; analgesic and sedative interventions; and the incidence of delirium before and after continuous ketamine infusion in patients who were admitted to medical and cardiac ICUs and received mechanical ventilation.

Study design
We conducted a retrospective cohort study between March 2012 and June 2020 at the Samsung Medical Center (a 1,989-bed tertiary referral hospital with tertiary-level ICUs) in Seoul, South Korea. We screened all patients aged 18 years or older who were admitted to medical and cardiac ICUs over 24 h. The admission units were decided according to main problems and underlying co-morbidities. Patients who received mechanical ventilation via tracheal intubation for over 24 h and continuous ketamine infusion for at least 8 h were included in the study. A total of 815 patients received continuous ketamine infusion during the study period. Patients who used concomitant neuromuscular blockers (n = 152) and ketamine for the non-sedation indication (n = 29), used ketamine for less than 8 h (n = 51), who were deceased or transferred within 24 h after the start of continuous ketamine infusion (n = 18), and had missing data (n = 1) were excluded. The remaining 564 eligible patients were analyzed (Fig 1).
The Institutional Review Board of the Samsung Medical Center approved this study and waived the requirement for informed consent because of the observational nature of the study. In addition, the patients' information was anonymized and de-identified before analysis.

Setting
The clinical practice guidelines published by the Society of Critical Care Medicine were adopted for general intensive care [1]. The institution did not have a protocol for patient selection for continuous ketamine infusion. In general, ketamine was added to conventional analgosedation infusions to optimize pain or sedation in patients who have failed conventional analgosedation or experienced adverse effects secondary to conventional analgosedation. The initiation of ketamine administration was based on the physician's discretion. When ketamine was started, a dosing protocol recommended a starting infusion of 2.0 mcg/kg/min to be titrated by 0.5 mcg/kg/min up to a maximum rate of 7.0 mcg/kg/min. According to the 2018 clinical practice guideline, we adjusted other opioids and sedatives to target a Richmond Agitation and Sedation Scale of -2 to +1 [1].

Data collection and clinical outcomes
Over the study period, all patients admitted to the medical or cardiac ICUs were prospectively registered. For this study, the data were supplemented with a retrospective review of electronic medical records. Demographic data, sequential organ failure assessment (SOFA) score, simplified acute physiology score 3, comorbidity, and diagnosis were collected at ICU admission. Serial data, including vital signs and the dose of vasopressors and inotropes were collected as average values before and after ketamine initiation. Serial data collection included 8 h before, time zero signifying ketamine initiation, and 8 h, 16 h, and 24 h post-ketamine initiation. vasoactive inotropic score (VIS) was calculated as: dopamine dose (μg/kg/min) + dobutamine dose (μg/kg/min) + 100 × epinephrine dose (μg/kg/min) + 10 × milrinone dose (μg/kg/min) + 10,000 × vasopressin dose (unit/kg/min) + 100 × norepinephrine dose (μg/kg/min) [7]. Due to the light sedation strategy, even in patients in controlled ventilation, the respiratory rate of the patient and the setting of respiratory rate on a mechanical ventilator may differ. Serial data were extracted using our institution's data repository (Clinical Data Warehouse Darwin-C, Samsung Medical Center, Seoul, Korea). Pain was evaluated using a critical care pain observation tool or numeric rating scale, and delirium was evaluated using the Richmond Agitation Sedation Scale and confusion assessment method for the ICU. Cardiac problems were defined as patients initially diagnosed with acute myocardial infarction, cardiogenic shock, complex arrhythmia, acute congestive heart failure with respiratory failure and/or requiring hemodynamic support, unstable angina, cardiac arrest, cardiac tamponade, dissecting aortic aneurysms, or complete heart block.
The primary outcome was immediate hemodynamic safety after continuous ketamine infusion. Hemodynamic safety was assessed by serial mean arterial blood pressure, heart rate, and respiratory rate changes. The secondary outcomes included immediate delirium, pain, and use of sedation.

Statistical analyses
Continuous variables were expressed as medians and interquartile ranges (IQRs) and examined using the Mann-Whitney U-test. Categorical variables were presented as numbers and percentages and analyzed using the Chi-square test or Fisher's exact test. Subgroup analysis was performed according to primary diagnosis, admitted ICU, and shock. The serial changes in the clinical variables were calculated using the Jonckheere-Terpstra test. All data were analyzed using SPSS version 22 (IBM Corp., Armonk, NY, USA).

Continuous ketamine infusion
The median VIS at the start of continuous ketamine infusion was 4.0 (0.0-18.2). Detailed analgosedation infusions at the start of ketamine administration are shown in Table 2

Before and after continuous ketamine infusion
Of the 564 patients, blood pressure and VIS did not change before and after continuous ketamine infusion (Fig 2, Table 3). Heart rate decreased significantly from 106.9 (91.4-120.9) at 8 h before ketamine initiation to 99.8 (83.9-114.4) at 24 h after ketamine initiation. In addition, the respiratory rate decreased significantly from 21.7 (18.6-25.4) at 8 h before ketamine initiation to 20.1 (17.0-23.0) at 24 h after ketamine initiation.
Subgroup analyses were also performed to investigate hemodynamic changes after continuous ketamine infusion according to the diagnosis at ICU admission. In patients who were admitted for respiratory failure (n = 324), blood pressure and VIS were not changed before and after continuous ketamine infusion, while heart rate and respiratory rate were decreased significantly: 107.  at 24 h after ketamine initiation for respiratory rate. The most surprising aspect of the data was in patients who were admitted with sepsis and cardiovascular problems. In patients who were admitted for sepsis (n = 110), arterial blood pressure was increased significantly after continuous ketamine infusion without increased VIS score: 70.0 (61.7-78.0) at 8 h before ketamine initiation to 73.2 (67.6-79.6) at 24 h after ketamine initiation for mean arterial blood pressure. Similar to patients with respiratory failure, heart rate and respiratory rate were significantly decreased. In addition, in patients who were admitted for cardiovascular problems (n = 94), arterial blood pressure also increased significantly after continuous ketamine infusion without increased VIS score, and heart rate and respiratory rate were significantly decreased.  The trends in pain, agitation, sedation, and delirium are shown in Table 4. No significant changes were observed in the prior-and post-ketamine initiation. The trends in pain, agitation, sedation, and delirium are evaluated according to clinical subgroups and presented in S2 Table. There were no significant changes prior-and post ketamine initiation whether in medical or cardiac ICU, sepsis, and shock. The analgesic and sedative interventions are presented in Table 5. Overall opioid usage was significantly reduced: 3.0 (0.0-6.0) mcg/kg/h as fentanyl equivalent dose at 8 h before ketamine initiation to 1.0 (0.0-4.1) mcg/kg/h as fentanyl equivalent dose in 24 h post-ketamine initiation. The use of remifentanil (p for trend = 0.010) and hydromorphone (p for trend = 0.010) were markedly reduced. However, the use of sedatives and antipsychotic medications did not decrease.

Discussion
This study evaluated serial hemodynamic, pain, agitation, sedation trends, and analgesic and sedative interventions before and after continuous ketamine infusion. Heart rate and respiratory rate decreased significantly without changing the mean blood pressure and VIS score. The trends in pain, agitation, sedation, and delirium did not change before and after continuous ketamine infusion. In analgesic and sedative interventions, a significant reduction in opioid use was observed, while sedatives and antipsychotic medications used similar prior-and post-continuous ketamine infusion.
Continuous ketamine infusion has been shown to reduce opioid requirements in patients with mechanical ventilation. Opioids are the cornerstone of pain management in critically ill patients. However, high cumulative doses of opioid use might be associated with opioid dependence, addiction, and hormonal changes [8]. Yaffe et al. analyzed 2,595 ICU survivors and reported that 12.2% of patients used opioids at hospital discharge, and 4.4% of survivors still used opioids up to 48 months of follow-up [9]. Academia and colleagues reviewed a total of 71 mechanically ventilated patients and reported that more than a third of opioid-naïve patients were discharged with large amounts of opioids after an ICU stay [10]. Therefore, the 2018 clinical practice guidelines recommend the use of non-opioid analgesics as adjunctive pain medications. Several studies of ketamine infusion in ICU patients have revealed that the use of lowdose ketamine as an adjunct to opioid therapy may help reduce opioid consumption, especially in surgical patients [11][12][13]. The study also found that continuous ketamine infusion reduced immediate opioid consumption in mechanically ventilated medical ICU patients. The present study suggests that continuous ketamine infusion might be helpful for non-opioid analgesics in critically ill patients. Recent meta-analysis for evaluation the impact of ketamine on opioids and sedatives consumption in critically ill patients also found similar results [14]. Some studies found that ketamine infusion reduced the use of benzodiazepine in critically ill patients [6,15]. However, this study did not show a decrease in sedative requirements for patients on mechanical ventilation. Due to the small number of patients receiving sedatives, the effect of ketamine infusion on sedative requirement may not be fully evaluated in this study.
To date, the usefulness of ketamine infusion in sepsis is known, with several pieces of evidence. Recent studies on ketamine infusion have reported its anti-inflammatory effects. Sun et al. investigated the protective effect of ketamine in vivo and showed that ketamine suppressed the production of tumor necrosis factor-alpha and interleukin-6 via inhibition of nuclear factor-κB in the intestine [16]. In addition, ketamine has been shown to reduce leukocyte recruitment, downregulate iNOS and cyclooxygenase-2, and upregulate anti-inflammatory markers such as heme oxygenase-1 [17,18]. In clinical practice, ketamine infusion has been reported to increase catecholamine levels, which may be associated with increased sympathetic activity and blood pressure [19,20]. In contrast, several studies have suggested that ketamine reduces left ventricular systemic and diastolic function in patients with ischemic heart disease or children [21,22]. A small study by Jakobsen et al. showed a decreased cardiac index after ketamine infusion in patients with heart failure despite an increase in mean arterial pressure and systemic vascular resistance [21]. In this study, mean arterial blood pressure tended to increase after continuous ketamine infusion in patients with sepsis and cardiovascular problems (p = 0.044 and p = 0.041, respectively; Fig 2). Further research should be undertaken to investigate the long-term trend of hemodynamic changes after continuous ketamine infusion in patients with sepsis and cardiovascular problems. More recently, studies have emerged that offer contradictory findings about the association between ketamine and delirium. A recent randomized controlled trial of patients undergoing cardiac surgery with cardiopulmonary bypass reported that intraoperative ketamine-based anesthesia significantly reduced postoperative delirium compared to propofol-based anesthesia [23]. In addition, a meta-analysis of the effects of ketamine on mechanically ventilated patients also reported a lower incidence of delirium in patients with ketamine than in those without ketamine [4]. Meanwhile, a secondary analysis study of a large ICU cohort of 925 patients reported that ketamine in critically ill patients may increase the risk of ICU delirium (adjusted odds ratio 5.60; 95% confidence interval, 1.09-29.15) [24]. However, some studies have reported that ketamine did not affect the incidence of delirium [25,26]. In this study, we also found that ketamine did not affect the incidence of delirium within 24 h after ketamine infusion in medical or cardiac critically ill patients. However, this result is limited by shortterm observations. Considering that ketamine was associated with hallucinations, sleep disturbances, and nightmares, more research with long-term observation after ketamine infusion is needed to clarify the association between ketamine and delirium. In this study, 324 patients with respiratory failure were included, and these patients showed a reduced respiratory rate compared to that before continuous ketamine infusion. A possible explanation for this might be that the patients became more sedated after ketamine infusion. Ketamine has favorable characteristics for patients with respiratory failure, including maintenance of respiratory drive and airway reflexes and bronchodilation [27,28]. However, a recent randomized control trial showed that ketamine infusion was not associated with improvement in ventilator variables associated with bronchospasm [29]. The effect of ketamine on mechanically ventilated patients has been extended during the coronavirus disease 2019 (COVID-19) pandemic due to the long duration of mechanical ventilation and the possibility of other sedative shortage to keep acute respiratory failure patients on mechanical ventilatory support [30,31]. Several comments on analgesia and sedation strategies in mechanically ventilated patients with COVID-19 recommend ketamine as an alternative drug for sedation [31,32]. Experience with ketamine infusion in patients with COVID-19 may help to better understand the impact of ketamine on mechanically ventilated patients.
Although this study provides additional information on continuous ketamine infusion in mechanically ventilated patients, several limitations should be acknowledged. First, this was a retrospective cohort study conducted in a single referral hospital. Although general ICU management was conducted according to general guidelines, the generalizability of our findings to other settings may be limited. In addition, vital signs and medications can be assessed by reviewing an electrical medical record. Multi-center prospective studies are needed to clarify the effects of ketamine infusion in medical or cardiac patients. Second, we did not include long-term serial data on hemodynamic changes, pain, agitation, and sedation. A prospective study with long-term serial monitoring data is needed to confirm the safety and usefulness of continuous ketamine infusion in critically ill mechanically ventilated patients. Third, this study was not specifically designed to evaluate detailed clinical information including inflammatory markers, and the results of echocardiography which might present immediate effect of ketamine infusion. Finally, we did not collect data on the adverse effects of ketamine, including anxiety, nightmares, sleep disturbance, increased salivation, and frequent suction. However, we found that ketamine did not increase the incidence of delirium within 24 h after ketamine infusion. Further well-designed prospective studies for evaluation of feasibility of ketamine infusion in medical and cardiac ICU patients should include detailed clinical information.

Conclusion
After ketamine infusion, heart rate and respiratory rate decreased significantly without changing the mean blood pressure and VIS score. In addition, a significant reduction in opioid use was observed. However, the incidence of delirium did not significantly increase within 24 h after ketamine infusion. This finding highlights that ketamine may be a safe and feasible analgesic for medical and cardiac ICU patients who received mechanical ventilation support.
Supporting information S1